U.S. patent application number 10/523419 was filed with the patent office on 2005-09-15 for storage stable tablets of fosinopril sodium.
Invention is credited to Kumar, Pananchukunnath Manoj, Malik, Rajiv, Mathur, Rajeev Shankar, Sethi, Sanjeev.
Application Number | 20050202083 10/523419 |
Document ID | / |
Family ID | 31503918 |
Filed Date | 2005-09-15 |
United States Patent
Application |
20050202083 |
Kind Code |
A1 |
Kumar, Pananchukunnath Manoj ;
et al. |
September 15, 2005 |
Storage stable tablets of fosinopril sodium
Abstract
The technical field of the present invention relates to the
selection of lubricants to provide a storage stable tablet of
fosinopril, alone or in combination with a diuretic, as well as
processes of preparation of the stable tablets. In particular, the
lubricants are a combination of colloidal silicon dioxide and
talc.
Inventors: |
Kumar, Pananchukunnath Manoj;
(Apartments, IN) ; Mathur, Rajeev Shankar; (Delhi,
IN) ; Sethi, Sanjeev; (Haryana, IN) ; Malik,
Rajiv; (Delhi, IN) |
Correspondence
Address: |
RANBAXY INC.
600 COLLEGE ROAD EAST
SUITE 2100
PRINCETON
NJ
08540
US
|
Family ID: |
31503918 |
Appl. No.: |
10/523419 |
Filed: |
February 1, 2005 |
PCT Filed: |
August 1, 2003 |
PCT NO: |
PCT/IB03/03113 |
Current U.S.
Class: |
424/464 ;
514/102 |
Current CPC
Class: |
A61K 31/675 20130101;
A61P 9/04 20180101; A61K 9/2009 20130101; A61P 9/12 20180101; A61K
9/2027 20130101; A61K 45/06 20130101; A61K 9/2018 20130101; A61K
31/675 20130101; A61K 9/2054 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/464 ;
514/102 |
International
Class: |
A61K 031/66; A61K
009/20 |
Claims
We claim:
1. A storage stable fosinopril tablet comprising fosinopril and a
combination of colloidal silicon dioxide and talc.
2. The storage stable tablet of claim 1, wherein the fosinopril
comprises one or more of free fosinopril acid and pharmaceutically
acceptable salts of fosinopril.
3. The storage stable tablet of claim 2, wherein the
pharmaceutically acceptable salt of fosinopril comprises one or
more of fosinopril sodium, fosinopril magnesium and fosinopril
calcium.
4. The storage stable tablet of claim 3, wherein the
pharmaceutically acceptable salt comprises fosinopril sodium.
5. The storage stable tablet of claim 1, wherein the colloidal
silicon dioxide comprises from about 0.25% to about 10% by weight
of the total tablet weight.
6. The storage stable tablet of claim 1, wherein the talc comprises
from about 0.25% to about 5% by weight of the total tablet
weight.
7. The storage stable tablet of claim 1, wherein the tablet further
comprises one or more pharmaceutically acceptable excipients.
8. The storage stable tablet of claim 7, wherein the one or more
pharmaceutically acceptable excipients comprise one or more of
diluent, disintegrant, binder, coloring agent, and flavoring
agent.
9. The storage stable tablet of claim 8, wherein the diluent
comprises one or more of calcium carbonate, calcium
phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,
cellulose-microcrystalline, cellulose powdered, dextrates,
dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose,
mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar
compressible and sugar confectioners.
10. The storage stable tablet of claim 9, wherein the diluent
comprises lactose.
11. The storage stable tablet of claim 8, wherein the binder
comprises one or more of methyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum
arabic, ethyl cellulose, polyvinyl alcohol, pullulan,
pregelatinized starch, agar, tragacanth, alginic acid derivatives
and propylene glycol, and alginate.
12. The storage stable tablet of claim 11, wherein the binder
comprises polyvinylpyrrolidone.
13. The storage stable tablet of claim 8, wherein the disintegrant
comprises one or more of low substituted hydroxypropyl cellulose,
carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium
carboxymethyl cellulose, croscarmellose sodium, starch, crystalline
cellulose, hydroxypropyl starch, and partly pregelatinized
starch.
14. The storage stable tablet of claim 13, wherein the disintegrant
comprises croscarmellose sodium.
15. The storage stable tablet of claim 1, wherein the tablet
further comprises one or more additional active ingredients.
16. The storage stable tablet of claim 15, wherein the one or more
additional active ingredients comprise a diuretic comprising one or
more of chlorthalidone, furosemide, triameterene, amiloride,
spironolactone, and thiazide diuretics.
17. The storage stable tablet of claim 16, wherein the thiazide
diuretic comprises one or more of chlorothiazide,
hydrochlorothiazide, flumethiazide and bendroflumethiazide.
18. The storage stable tablet of claim 17 wherein the thiazide
diuretic comprises hydrochlorothiazide.
19. The storage stable tablet of claim 15, wherein the one or more
additional active ingredients comprise one or more of
antidepressants, antidiabetics, antiulcers, analgesics,
antihypertensives, antibiotics, antipsychotics, antineoplastics,
antimuscarinics, diuretics, antimigraine agents, antivirals,
anti-inflammatory agents, sedatives, antihistaminics, antiparasitic
agents, antiepileptics and lipid lowering agents.
20. The storage stable tablet of claim 15, wherein the one or more
additional active ingredients comprise one or more of enalapril,
captopril, benazepril, lisinopril, ranitidine, famotidine,
ranitidine bismuth citrate, diltiazem, propranolol, verapamil,
nifedipine, acyclovir, ciprofloxacin, simvastatin, atorvastatin,
lovastatin, divalproex, venlafaxine, citalopram, paroxetine,
selegiline, midazolam, fluoxetine, acarbose, buspirone, ninesulide,
captopril, nabumetone, glimepiride, glipizide, etodolac, nefazodone
and their pharmaceutically acceptable salts.
21. The storage stable tablet of claim 1, wherein greater than
approximately 98% of an initial amount of fosinopril sodium remains
after storage for three months at 40.degree. C. and 75% relative
humidity as measured by high performance liquid chromatography.
22. The storage stable tablet of claim 1, wherein greater than
approximately 98% of an initial amount of fosinopril sodium remains
after storage for one week at 60.degree. C. as measured by high
performance liquid chromatography.
23. The storage stable tablet of claim 22, wherein greater than
approximately 99% of an initial amount of fosinopril sodium remains
after storage for one week at 60.degree. C. as measured by high
performance liquid chromatography.
24. The storage stable tablet of claim 1, wherein greater than
approximately 98% of an initial amount of fosinopril sodium remains
after storage for one week at 60.degree. C. as measured by high
performance liquid chromatography.
25. The storage stable table of claim 7, wherein the tablet
comprises approximately 20% by weight of fosinopril sodium,
approximately 45% by weight of anhydrous lactose, approximately 20%
by weight of microcrystalline cellulose, approximately 3.5% by
weight of crospovidone, approximately 5% by weight of
polyvinylpyrrolidone, approximately 2.5% by weight of colloidal
silicon dioxide, and approximately 4.0% by weight of talc.
26. A storage stable fosinopril tablet comprising: from about 1% to
about 40% by weight fosinopril sodium; up to 25% by weight of a
diuretic; from about 20% to about 85% by weight of diluent; from
about 1% to about 10% by weight of disintegrant; from about 1% to
about 10% by weight of binder; from about 0.25% to about 10% by
weight of colloidal silicon dioxide; and from about 0.25% to about
5% by weight of talc, wherein the weights are percentages of the
total tablet weight.
27. A process for preparing storage stable fosinopril tablets, the
process comprising the steps of: a. blending fosinopril in one or
more of its free acid form and its pharmaceutically acceptable
salts with one or more pharmaceutically acceptable excipients to
form a blend, b. optionally granulating the blend to form granules;
c. lubricating the blend or granules with colloidal silicon dioxide
and talc; and d. compressing into tablets.
28. The process according to claim 27, further comprising
granulating the blend of step (a).
29. The process according to claim 28, wherein granulating the
blend of step (a) comprises a wet granulation process.
30. The process according to claim 28, wherein granulating the
blend of step (a) comprises a dry granulation process.
31. The process according to claim 27, wherein the blend of step
(a) further comprises one or more additional active
ingredients.
32. The process according to claim 31, wherein the additional
active ingredient comprises one or more of a diuretic comprising
chlorthalidone, furosemide, triameterene, amiloride,
spironolactone, and thiazide diuretics.
33. The process according to claim 32, wherein the thiazide
diuretic comprises one or more of chlorothiazide,
hydrochlorothiazide, flumethiazide and bendroflumethiazide.
34. The process according to claim 33, wherein the thiazide
diuretic comprises hydrochlorothiazide.
35. The process according to claim 27, further comprising using
high performance liquid chromatography to measure the amount of
fosinopril after storage.
36. The process according to claim 35, wherein greater than
approximately 98% of an initial amount of fosinopril remains after
storage for three months at 40.degree. C. and 75%, the amount of
fosinopril being measured by high performance liquid
chromatography.
37. The process according to claim 35, wherein greater than
approximately 99% of an initial amount of fosinopril remains after
storage for one week at 60.degree. C., the amount of fosinopril
being measured by high performance liquid chromatography.
38. A method for one or more of treating hypertension in a mammal
and the management of heart failure as an adjunctive therapy in a
mammal, the method comprising administering to the mammal one or
more fosinopril tablets comprising fosinopril in one or more of its
free acid form and its pharmaceutically acceptable salts, colloidal
silicon dioxide, and talc.
39. The method according to claim 38, wherein the tablet further
comprises a second active ingredient.
40. The method according to claim 39, wherein the second active
ingredient comprises a diuretic comprising one or more of
chlorthalidone, furosemide, triameterene, amiloride,
spironolactone, and thiazide diuretics.
41. The method according to claim 40, wherein the thiazide diuretic
comprises one or more of chlorothiazide, hydrochlorothiazide,
flumethiazide and bendroflumethiazide.
42. The method according to claim 41, wherein the thiazide diuretic
comprises hydrochlorothiazide.
43. The method according to claim 38, wherein greater than
approximately 98% of an initial amount of fosinopril remains after
storage for three months at 40.degree. C. and 75% relative humidity
as measured by high performance liquid chromatography.
44. The storage stable tablet of claim 38, wherein greater than
approximately 99% of an initial amount of fosinopril sodium remains
after storage for one week at 60.degree. C. as measured by high
performance liquid chromatography.
Description
FIELD OF THE INVENTION
[0001] The technical field of the present invention relates to the
selection of lubricants to provide a storage stable tablet of
fosinopril, alone or in combination with a diuretic, as well as
processes of preparation of the stable tablets.
BACKGROUND OF THE INVENTION
[0002] Fosinopril is the ester prodrug of the angiotensin
converting enzyme inhibitor, fosinoprilat. Fosinopril alone or in
combination with a diuretic, particularly a thiazide diuretic is
indicated for the treatment of hypertension. It is also used as an
adjunctive therapy for the management of heart failure as part of a
conventional therapy that includes diuretics and, optionally,
digitalis.
[0003] Fosinopril and its pharmaceutically acceptable salts, and in
particular the sodium salt, have a low bulk density, poor flow
characteristics, and a tendency to stick to metal surfaces. The
combination of the above characteristics makes the manufacturing of
tablets highly problematic and, in particular, makes necessary the
careful selection and incorporation of suitable lubricants. In
addition, the hydrolytic nature of fosinopril further complicates
the selection of other pharmaceutically acceptable excipients.
[0004] In the past, conventional fosinopril sodium tablets were
prepared using magnesium stearate as the lubricant. However, these
tablets were highly sensitive to moisture and only marginally
stable. Therefore, in order to achieve reasonable shelf lives these
tablets required sophisticated protective packaging.
[0005] The above problem of selecting a suitable lubricant is
addressed in U.S. Pat. No. 5,006,344 which discloses the use of
either sodium stearyl fumarate or hydrogenated vegetable oil as the
lubricant to prepare tablets with improved stability. Both of these
compounds are long chain organic molecules. For example, according
to the Handbook of Pharmaceutical Excipients. Third Edition (2000),
the formula for sodium stearyl fumarate is
C.sub.22H.sub.39NaO.sub.4 and the formula for hydrogenated
vegetable oil is R.sub.1COOCH.sub.3--CH(OOCR.sub.2)--CH.sub.-
2OOCR.sub.3.
SUMMARY OF THE INVENTION
[0006] In one general aspect there is provided a stable fosinopril
tablet comprising fosinopril alone or in combination with a
diuretic.
[0007] In another general aspect, there is provided a storage
stable fosinopril tablet comprising fosinopril and a combination of
colloidal silicon dioxide and talc.
[0008] Embodiments of the storage stable fosinopril tablet may
include one or more of the following features. For example, the
fosinopril may be one or more of free fosinopril acid and
pharmaceutically acceptable salts of fosinopril. The
pharmaceutically acceptable salt of fosinopril may be one or more
of fosinopril sodium, fosinopril magnesium and fosinopril calcium.
The pharmaceutically acceptable salt may be fosinopril sodium. The
colloidal silicon dioxide may be from about 0.25% to about 10% by
weight of the total tablet weight. The talc may be from about 0.25%
to about 5% by weight of the total tablet weight.
[0009] The storage stable tablet may further include one or more
pharmaceutically acceptable excipients and the one or more
pharmaceutically acceptable excipients may be one or more of
diluent, disintegrant, binder, coloring agent, and flavoring agent.
The diluent may be one or more of calcium carbonate, calcium
phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,
cellulose-microcrystalline, cellulose powdered, dextrates,
dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose,
mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar
compressible and sugar confectioners, and in particular may be
lactose. The binder may be one or more of methyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose,
polyvinyl alcohol, pullulan, pregelatinized starch, agar,
tragacanth, alginic acid derivatives and propylene glycol, and
alginate, and in particular may be polyvinylpyrrolidone. The
disintegrant may be one or more of low substituted hydroxypropyl
cellulose, carboxymethyl cellulose, calcium carboxymethyl
cellulose, sodium carboxymethyl cellulose, croscarmellose sodium,
starch, crystalline cellulose, hydroxypropyl starch, and partly
pregelatinized starch, and in particular may be croscarmellose
sodium.
[0010] The storage stable tablet may further include one or more
additional active ingredients and the one or more additional active
ingredients may be a diuretic including one or more of
chlorthalidone, flirosemide, triameterene, amiloride,
spironolactone, and thiazide diuretics. The thiazide diuretic may
be one or more of chlorothiazide, hydrochlorothiazide,
flumethiazide and bendroflumethiazide, and the thiazide diuretic
may be hydrochlorothiazide.
[0011] The one or more additional active ingredients also may be
one or more of antidepressants, antidiabetics, antiulcers,
analgesics, antihypertensives, antibiotics, antipsychotics,
antineoplastics, antimuscarinics, diuretics, antimigraine agents,
antivirals, anti-inflammatory agents, sedatives, antihistaminics,
antiparasitic agents, antiepileptics and lipid lowering agents. The
one or more additional active ingredients may be one or more of
enalapril, captopril, benazepril, lisinopril, ranitidine,
famotidine, ranitidine bismuth citrate, diltiazem, propranolol,
verapamil, nifedipine, acyclovir, ciprofloxacin, simvastatin,
atorvastatin, lovastatin, divalproex, venlafaxine, citalopram,
paroxetine, selegiline, midazolam, fluoxetine, acarbose, buspirone,
nimesulide, captopril, nabumetone, glimepiride, glipizide,
etodolac, nefazodone and their pharmaceutically acceptable
salts.
[0012] More than approximately 98% of an initial amount of
fosinopril sodium may remain after storage for three months at
40.degree. C. and 75% relative humidity as measured by high
performance liquid chromatography. More than approximately 98% to
99% of an initial amount of fosinopril sodium may remain after
storage for one week at 60.degree. C. as measured by high
performance liquid chromatography.
[0013] The storage stable table may include approximately 20% by
weight of fosinopril sodium, approximately 45% by weight of
anhydrous lactose, approximately 20% by weight of microcrystalline
cellulose, approximately 3.5% by weight of crospovidone,
approximately 5% by weight of polyvinylpyrrolidone, approximately
2.5% by weight of colloidal silicon dioxide, and approximately 4.0%
by weight of talc.
[0014] In another general aspect, a storage stable fosinopril
tablet includes from about 1% to about 40% by weight fosinopril
sodium; up to 25% by weight of a diuretic; from about 20% to about
85% by weight of diluent; from about 1% to about 10% by weight of
disintegrant; from about 1% to about 10% by weight of binder; from
about 0.25% to about 10% by weight of colloidal silicon dioxide;
and from about 0.25% to about 5% by weight of talc. The weights are
percentages of the total tablet weight.
[0015] Embodiments of the storage stable fosinopril tablet may
include any of the features described herein.
[0016] In another general aspect, a process for preparing storage
stable fosinopril tablets includes the steps of (a) blending
fosinopril in one or more of its free acid form and its
pharmaceutically acceptable salts with one or more pharmaceutically
acceptable excipients to form a blend, (b) optionally granulating
the blend to form granules; (c) lubricating the blend or granules
with colloidal silicon dioxide and talc; and (d) compressing into
tablets.
[0017] Embodiments of the process may include any one of the
features described herein. For example, the process may further
include granulating the blend of step (a) and granulating the blend
of step (a) may be a wet granulation process or a dry granulation
process.
[0018] The blend of step (a) may further include one or more
additional active ingredients. The additional active ingredient may
be one or more of a diuretic comprising chlorthalidone, furosemide,
triameterene, amiloride, spironolactone, and thiazide diuretics.
The thiazide diuretic may be one or more of chlorothiazide,
hydrochlorothiazide, flumethiazide and bendroflumethiazide, and in
particular hydrochlorothiazide.
[0019] The process may further include using high performance
liquid chromatography to measure the amount of fosinopril after
storage. Greater than approximately 98% of an initial amount of
fosinopril may remain after storage for three months at 40.degree.
C. and 75%, the amount of fosinopril being measured by high
performance liquid chromatography. Greater than approximately 99%
of an initial amount of fosinopril may remain after storage for one
week at 60.degree. C., the amount of fosinopril being measured by
high performance liquid chromatography.
[0020] In another general aspect, a method for one or more of
treating hypertension in a mammal and the management of heart
failure as an adjunctive therapy in a mammal includes administering
to the mammal one or more fosinopril tablets that include
fosinopril in one or more of its free acid form and its
pharmaceutically acceptable salts, colloidal silicon dioxide, and
talc.
[0021] Embodiments of the method may include any one of the
features described herein. For example, the tablet may further
include a second active ingredient and the second active ingredient
may be a diuretic including one or more of chlorthalidone,
furosemide, triameterene, amiloride, spironolactone, and thiazide
diuretics. The thiazide diuretic comprises one or more of
chlorothiazide, hydrochlorothiazide, flumethiazide and
bendroflumethiazide and in particular the thiazide diuretic may be
hydrochlorothiazide.
[0022] Greater than approximately 98% of an initial amount of
fosinopril may remain after storage for three months at 40.degree.
C. and 75% relative humidity as measured by high performance liquid
chromatography. Greater than approximately 99% of an initial amount
of fosinopril sodium remains after storage for one week at
60.degree. C. as measured by high performance liquid
chromatography.
[0023] In another general aspect there is provided a stable
fosinopril tablet comprising fosinopril, and a combination of
colloidal silicon dioxide and talc as lubricant wherein colloidal
silicon dioxide may vary from about 0.25% to about 10% by weight
and talc about 0.25% to about 5% by weight, of the total tablet
weight.
[0024] In another general aspect there is provided a stable
fosinopril tablet comprising fosinopril, a diuretic, and a
combination of colloidal silicon dioxide and talc as lubricant
wherein colloidal silicon dioxide may vary from about 0.25% to
about 10% by weight and talc about 0.25% to about 5% by weight, of
the total tablet weight.
[0025] In another general aspect there is provided a method for the
management of heart failure in a mammal by administering as
adjunctive therapy to the said mammal fosinopril tablet comprising
fosinopril, a diuretic, colloidal silicon dioxide and talc.
[0026] The details of one or more embodiments of the inventions are
set forth in the description below. Other features, objects, and
advantages of the invention will be apparent from the description
and claims.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The inventors have now discovered that the use of a
combination of talc and colloidal silicon dioxide in the
formulation functions surprisingly well as lubricants during the
tableting process and further surprisingly increases the stability
of the tablet and provides reasonably long shelf lives for the thus
formed fosinopril tablets. Advantageously, these benefits result
even at low concentrations of the colloidal silicon dioxide and
talc. In contrast to the very long chain organic molecules
described above as lubricants, the Handbook of Pharmaceutical
Excipients, Third Edition (2000) describes colloidal silicon
dioxide and talc as inorganic molecules that have, for example, the
molecular formulae SiO.sub.2 and
Mg.sub.6(Si.sub.2O.sub.5).sub.4(OH).- sub.4, respectively, although
for purposes of the inventions described herein, variations and
other forms of silicon dioxide and talc are intended to be
encompassed within these terms.
[0028] Conventionally, colloidal silicon dioxide and talc are used
as glidants. However, to the inventors' surprise the combination of
the two showed excellent lubricant properties and, relevant to
problems in formulating dosage forms of fosinopril, the tablets
thus prepared had improved shelf stability. Colloidal silicon
dioxide or talc used individually in higher concentrations may also
provide proper lubrication during processing of tablets and
stability during storage. However, moving to higher concentrations
of lubricant increases the tablet weight and may also exceed the
permissible daily intake of the lubricant. Further, the higher
concentration of lubricant may also hamper the dissolution of the
drug from the tablets and consequently the bioavailability of the
drug. The combination of colloidal silicon dioxide and talc, on the
other hand, appear to have a synergistic action and is therefore
effective in reasonably low amounts. When used in combination, the
amount of talc may vary from about 0.25% to about 5% by weight and
the amount of colloidal silicon dioxide may vary from about 0.25%
to about 10% by weight with respect to the total weight of
tablet.
[0029] Comparative stability results were generated under two
conditions: (1) at 40.degree. C. and 75% relative humidity over a
period of three months (see Table 1, below) and (2) at 60.degree.
C. for one week (see Table 2, below). The results were generated
for fosinopril tablets that included a combination of colloidal
silicon dioxide and talc as lubricants and for the marketed
Monopril.RTM. tablets. The results indicate the benefits of using a
combination of colloidal silicon dioxide and talc as the fosinopril
tablet lubricant.
[0030] The term "fosinopril" as used herein includes both the free
acid form as well as its pharmaceutically acceptable salts, such as
those with sodium, magnesium, calcium, etc. In particular,
fosinopril sodium may be used. The concentration of fosinopril
sodium may vary from about 1% to about 40% by weight of the total
tablet weight.
[0031] Stable fosinopril tablets may also include a second active
ingredient, and particularly may include a diuretic. Examples of
suitable diuretics include chlorthalidone, furosemide,
triameterene, amiloride, spironolactone, thiazide diuretics, and
the like. Suitable examples of thiazide diuretics include
chlorthiazide, hydrochlorthiazide, flumethiazide,
bendroflumethiazide, and the like. The concentration of diuretic
may vary up to about 25% by weight of the total tablet weight.
[0032] In addition to the tablet including fosinopril as an active
ingredient, and colloidal silicon dioxide and talc as the
lubricant, fosinopril tablets may also include pharmaceutically
acceptable excipients. The term "pharmaceutically acceptable inert
excipients" as used herein includes all excipients used in the art
of manufacturing tablets.
[0033] Examples of pharmaceutically acceptable excipients include
binders, diluents, disintegrants, coloring agents, flavoring
agents, and the like.
[0034] Examples of suitable diluents include calcium carbonate,
calcium phosphate-dibasic, calcium phosphate-tribasic, calcium
sulfate, cellulose-microcrystalline, cellulose powdered, dextrates,
dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose,
mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar
compressible, sugar confectioners, and the like. The concentration
of diluent may vary from about 20% to about 85% by weight of the
total tablet weight.
[0035] Examples of suitable binders include methyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose,
polyvinyl alcohol, pullulan, pregelatinized starch, agar,
tragacanth, alginic acid derivatives, propylene glycol and the
like. The concentration of binder may vary from about 1% to about
10% by weight of the total tablet weight.
[0036] Examples of suitable disintegrants include low substituted
hydroxypropyl cellulose, carboxymethyl cellulose, calcium
carboxymethyl cellulose, sodium carboxymethyl cellulose,
croscarmellose sodium A-type (Ac-di-sol), starch, crystalline
cellulose, hydroxypropyl starch, partly pregelatinized starch, and
the like. The concentration of disintegrant may vary from about 1%
to about 10% by weight of the total tablet weight.
[0037] Suitable coloring agents and flavoring agents include FDA
approved colors and flavors for oral use that are compatible with
the other ingredients of the tablet.
[0038] The stable fosinopril tablet may be prepared by processes
known in the pharmaceutical arts, for example, by comminuting,
mixing, granulation, melting, sizing, filling, drying, molding,
immersing, coating, compressing, etc. Examples of specific
processes suitable for preparing the tablets include wet
granulation, dry granulation and direct compression.
[0039] In one of the processing embodiments, a wet granulation
process of preparing the tablets includes the steps of blending
fosinopril sodium and, optionally, a diuretic with one or more
diluents and disintegrants; granulating the blend with a
solution/dispersion of one or more binders in one or more suitable
solvents; drying and sieving the granules; lubricating the blend
with talc and colloidal silicon dioxide; and compressing into
tablets. Specific examples of suitable solvents for preparing the
solution/dispersion of binder include one or more of methylene
chloride, isopropyl alcohol, acetone, methanol, ethanol, water and
the like.
[0040] In another processing embodiment, a direct compression
process for preparing the tablets includes the steps of blending
fosinopril sodium and, optionally, a diuretic with one or more
diluents, disintegrants and binders; lubricating the blend with
talc and colloidal silicon dioxide; and compressing into
tablets.
[0041] In another processing embodiment, a dry granulation process
for preparing the tablets includes the steps of blending fosinopril
sodium and, optionally, a diuretic with one or more diluents,
binders and disintegrants; dry granulating the blend by slugging or
roller compaction; lubricating the blend with talc and colloidal
silicon dioxide; and compressing into tablets.
[0042] The fosinopril tablets prepared by any of the above methods
may optionally be coated with one or more functional and/or
non-functional coatings, if desired.
[0043] The following examples further exemplify the inventions and
are not intended to limit the scope of the inventions.
FORMULATIONS OF EXAMPLES 1-3
[0044]
1 Amount (mg/tablet) Ingredients Example 1 Example 2 Example 3
Fosinopril Sodium 40.0 20.0 20.0 Hydrochlorthaizide -- 12.5 12.5
Anhydrous Lactose 90.0 32.5 97.5 Microcrystalline Cellulose 40.0
20.0 40.0 Crospovidone 7.0 3.5 7.0 Polyvinylpyrrolidone 10.0 5.0
10.0 Colloidal Silicon Dioxide 5.0 2.5 5.0 Talc 8.0 4.0 8.0
Isopropyl Alcohol qs qs qs
[0045] Process:
[0046] 1. Fosinopril sodium and hydrochlorthiazide (Examples 2 and
3) were blended with lactose, microcrystalline cellulose and a
portion of the crospovidone.
[0047] 2. The blend of step 1 was granulated with
polyvinylpyrrolidone solution in isopropyl alcohol.
[0048] 3. The granules obtained above were dried and blended with
crospovidone, talc and colloidal silicon dioxide.
[0049] 4. The lubricated blend of step 3 was compressed into
suitably sized tablets.
[0050] As evident from the formulation data above, a tablet
according to Example 1 includes approximately 20% by weight of
fosinopril sodium, approximately 45% by weight of anhydrous
lactose, approximately 20% by weight of microcrystalline cellulose,
approximately 3.5% by weight of crospovidone, approximately 5% by
weight of polyvinylpyrrolidone, approximately 2.5% by weight of
colloidal silicon dioxide, and approximately 4.0% by weight of
talc. Fosinopril tablets prepared with the formulation of Example 1
were analyzed for the initial amount of fosinopril sodium using an
in-house validated high performance liquid chromatography (HPLC)
method. One batch of these samples was then kept at 40.degree. C.
and 75% relative humidity for three months. The amount of
fosinopril sodium at the end of the first, the second and the third
month was analyzed to determine the amount of fosinopril sodium;
the results obtained are listed in Table 1. Another batch of these
samples was kept at 60.degree. C. for one week and then was
analyzed to determine the amount of fosinopril sodium; the results
obtained at one week are listed in Table 2.
2TABLE 1 Stability results generated after storage at 40.degree. C.
and 75% relative humidity Amount of Fosinopril sodium (mg) After 1
month After 2 month After 3 month at 40.degree. C. and at
40.degree. C. and at 40.degree. C. and 75% relative 75% relative
75% relative Tablets Initial humidity humidity humidity Fosinopril
40 39.69 39.98 39.23 tablets prepared per Example 1 "MONOPRIL"
40.01 -- -- 39.95 Commercially available fosinopril sodium tablets
(strength - 40 mg) of BRISTOL MYERS SQUIBB
[0051]
3TABLE 2 Stability results generated after storage at 60.degree. C.
Amount of Fosinopril sodium (mg) Tablets Initial After one week at
60.degree. C. Fosinopril tablets prepared as per the 40.01 39.95
Example 1 "MONOPRIL" Commercially available 40.01 39.79 fosinopril
sodium tablets (strength - 40 mg) of BRISTOL MYERS SQUIBB
[0052] As evident from the above stability data, after three months
storage at 40C and 75% relative humidity, the fosinopril sodium
tablets made according to the formulation of Example 1 were stable,
e.g., greater than approximately 98% of the fosinopril sodium
remained. Similarly, after one week storage at 60C, the fosinopril
sodium tablets made according to the formulation of Example 1 were
stable, e.g., greater than approximately 99% of the fosinopril
sodium remained.
[0053] While several particular forms of the inventions have been
described, it will be apparent that various modifications and
combinations of the inventions detailed in the text can be made
without departing from the spirit and scope of the inventions. For
example, the combination of colloidal silicon dioxide and talc can
be used as a lubricant with any active pharmaceutical ingredient
that is chemically and physically compatible with colloidal silicon
dioxide and talc. Examples of classes of active pharmaceutical
ingredients that may be used with the combination lubricant
described here include antidepressants, antidiabetics, antiulcers,
analgesics, antihypertensives, antibiotics, antipsychotics,
antineoplastics, antimuscarinics, diuretics, antimigraine agents,
antivirals, anti-inflammatory agents, sedatives, antihistaminics,
antiparasitic agents, antiepileptics and lipid lowering agents.
Illustrative examples of specific drugs of the above classes
include enalapril, captopril, benazepril, lisinopril, ranitidine,
famotidine, ranitidine bismuth citrate, diltiazem, propranolol,
verapamil, nifedipine, acyclovir, ciprofloxacin, simvastatin,
atorvastatin, lovastatin, divalproex, venlafaxine, citalopram,
paroxetine, selegiline, midazolam, fluoxetine, acarbose, buspirone,
nimesulide, captopril, nabumetone, glimepiride, glipizide,
etodolac, nefazodone and their pharmaceutically acceptable salts.
Further, it is contemplated that any single feature or any
combination of optional features of the inventive variations
described herein may be specifically excluded from the claimed
inventions and be so described as a negative limitation.
Accordingly, it is not intended that the inventions be limited,
except as by the appended claims.
* * * * *